Control Group Outcomes in Trials of Psilocybin, SSRIs, or Esketamine for Depression

Importance: Psilocybin has demonstrated rapid and sustained antidepressant efficacy, with acute-phase effect sizes often more than double those for conventional antidepressants. However, concerns have been raised that high rates of functional unblinding in combination with trial participants with positive expectations of psychedelic use might bias treatment outcomes.

Objective: To compare outcomes for patients receiving control treatments in randomized clinical trials of psilocybin for depression with control treatment outcomes from trials of selective serotonin reuptake inhibitors (SSRIs) and esketamine. Data Sources Two previous meta-analyses and 1 US Food and Drug Administration review published between March 2019 and December 2024 were used to identify double-blind trials on adult major depressive disorder (MDD) or treatment-resistant depression (TRD) that had a relevant control treatment arm and used the Montgomery-Åsberg Depression Rating Scale (MADRS) for symptom rating. Study Selection Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline, trials of psilocybin for MDD and TRD, esketamine for TRD, and a selective serotonin reuptake inhibitor (SSRI) for MDD were selected. Studies that included only individuals aged younger than 18 years or older than 65 years, used a crossover design, or had a duration less than 2 weeks were excluded. Data Extraction and Synthesis All authors assessed the 3 reviews for includable trials. Three authors independently extracted data for all trials, with disagreements resolved by consensus discussion. Data were pooled using random-effects models.

Main Outcomes and Measures: Standardized mean change (SMC) in MADRS scores from baseline to up to 6 weeks after randomization was used to assess within-group effect sizes, and standardized mean difference (SMD) was used to assess between-group effect sizes. Omnibus Test of Moderators (QM) was used to test whether the study population significantly moderated effect sizes.

Results: The study included 17 trials: 4 of psilocybin (n = 373), 2 of esketamine (n = 573), and 11 of SSRIs (n = 4014). Pretreatment to posttreatment SMCs (SEMs) were 1.21 (0.15) for psilocybin, 1.28 (0.06) for SSRIs, and 1.43 (0.15) for esketamine and were 0.50 (0.15), 1.00 (0.08), and 1.12 (0.17) for their respective control treatments. Study population was a significant moderator of between-group SMDs (QM, 10.7; df , 2; P = .005) and pre– to post–control treatment SMCs (QM, 10.4; df , 2; P = .005) but not of pre– to post–active treatment SMCs (QM, 1.21; df , 2; P = .55). MADRS response rates for control treatments in SSRI trials were 14 percentage points higher than in psilocybin trials and in esketamine trials were 23 percentage points higher than in psilocybin trials. Dropout rates for psilocybin (active treatment: 10 of 186 [5%]; control: 20 of 187 [11%]) and esketamine (active treatment: 43 of 349 [12%]; control: 18 of 224 [8%]) were similar and considerably lower than for SSRIs (active treatment: 866 of 2694 [32%]; control: 467 of 1320 [35%]). Conclusions and Relevance In this meta-analysis of control treatment outcomes in trials of psilocybin, SSRIs, or esketamine for depression, participants receiving control treatment in psilocybin trials had significantly less improvement in depression ratings than participants receiving control treatment in trials of SSRIs or esketamine. This might indicate that psilocybin’s antidepressant efficacy is overestimated compared with that of SSRIs and esketamine.